Selective dehalogenation of 6 alpha-fluoro-9 alpha-halo 11 beta-hydroxy steroids

ABSTRACT

6 Alpha -Fluoro-9 Alpha -(Cl, Br and I)-11 Beta -hydroxy- Delta 4-3-keto and Delta 1,4-3-keto steroids are selectively dehalogenated at the 9-position with trialkyltin hydride, preferably in the presence of free radicals.

nited States Patent [191 llsaurent et al,

[451 July 8,1975

[ SELECTIVE DEHALOGENATION OF 6 ALPHA-FLUORO-9 ALPHA-HALO llllBETA-HYDROXY STEROIDS [75] lnventors: Henry Laurent; Rudolf Wiechert,

both of Berlin, Germany [73] Assignee: Schering Alktiengesellschaft,Berlin,

Germany [22] Filed: Apr. 8, 1974 [21] Appl. No.: 459,098

[30] Foreign Application Priority Data Apr. 19, 1973 Germany 2320999[52] US. @l. 260/397.45 [51] lnt. Cl? C0'7c 169/32 [58] Field of Search260/397.45

[56] References Cited OTHER PUBLICATIONS Baston et al., J. Amer. Chem.Soc., 88, 1966, page 3016.

Primary ExaminerElbert L. Roberts Attorney, Agent, or FirmMillen, Raptes& White [57] ABSTRACT 8 Claims, No Drawings SELECTIVE DEHALOGENATION OF6 ALPHA-FLUOROQ ALPHA-HALO I1 BETA-HYDROXY STEROIDS BACKGROUND OF THEINVENTION This invention relates to a process for the selectivedehalogenation of 6a-fluoro-9cz-halo-l1B-hydroxy-3- keto-A -and ASt61'0ldS.

It is known that 9a-bromo-l lB-hydroxy-4-pregnene- 3,20-dione can bedebrominated with triphenyltin hydride (Barton et al., J. Amer. Chem.Soc. 88, 1966, 3016). If this reaction is conducted on a steroid havinga fiat-fluorine atom, the '6-fluorine atom is also substituted byhydrogen along with the halogen atom in the 9-position, as illustratedhereinafter. (See Example A.)

It is an object of the present invention to provide a processfor'selectively eliminating the halogen atom in the 9-position of a6a-fluoro-9a-(chloro-, bromo-, or iodo)-l lB-hydroxy-A -3-keto and A-keto steroids without attacking the fluorine atom in the 6-position.

SUMMARY OF THE INVENTION According to the process of this invention, the9- halogen of 6a-fluoro-9a-(chloro-, bromo-, oriodo)-llB-hydroxy-3-keto-A and A -steroids is selectively dehalogenatedwith a trialkyltin hydride, preferably in the presence of a freeradical-forming agent.

The steroid reaction products of the process of this invention can berepresented by the general partial Formula I wherein X is chlorine,bromine or iodine and C :C and D have the values given above, with atrialkyltin hydride, preferably in the presence of a free radicalformingagent.

DETAILED DISCUSSION It was surprising that, by using trialkyltinhydride, the chlorine, bromine or iodine atom in the 9oz-position isselectively eliminated and the fluorine atom in the 6ozposition is'notaffected. Analogously to the reaction with triphenyltin hydride, itwould be expected the flu orine atom would also be split off, especiallysince the latter is activated in its reactivity by its allyl positionrelative to the N-double bond.

The operability and utility of the process is not dependent upon theexact nature of the substituents on the lD-ring. Thus, the D-ring of thestarting steroids (and of the products) of the process of this inventioncan be substituted in the usual manner, preferably in the 17-position.Examples of such substituents are, for the androstane series, l7-keto,17B-hydroxy, 17/3- acyloxy, 17,8-ethyl, and for the pregnane series,1713- acetyl, l7B-hydroxyacetyl, l7/3-acyloxyacetyl, 17ahydroxy-17,8-acetyl, 1 7a-acyloxy-1 7,8-acetyl, 17ozhydroxyl "/B-hydroxyacetyl,lz-hydroxyl 7 B- acyloxyacetyl, l7oz-acyloxy-l7,8-acyloxyacetyl andl7B-( 2-hydroxypropionyl). The l6-position can also be substituted,e.g., by hydroxy or lower alkyl. Hydroxy groups in the 16- and 17- or inthe 17- and 2l-positions can be present in free, etherified oresterified form or part of a dialkylmethylenedioxy,cycloalkylidenedioxy, or arylalkylmethylenedioxy group. A 20-keto group,when present, can also be in the masked (blocked) form, for example, asethylene ketal or as the bis( alkylidenedioxy) compound in case of thehydrocortisone side chain.

Preferred starting steroids for the process of this invention aresteroids of the pregnane series of the general Formula III wherein R ishydrogen, hydroxy or acyloxy, R is hydrogen, hydroxy or acyloxy and R ishydrogen, methyl, hydroxy or acyloxy, especially those wherein acyl ineach instance is the acyl radical of a hydrocarbon carboxylic acid of2-12 carbon atoms, or R and R collec'-' tively aredialkylmethylenedioxy, especially those wherein alkyl is of l to 4carbon atoms, R, is hydrogen or methyl, and G L-C and X have the valuesgiven above.

Since the exact nature of the substituents on the D- ring is notcritical to the operability or utility of the process of this invention,obviously if such a substituent is or bears an acyloxy group, the exactnature of the acyloxy group is not critical.

Thus, the acyl and acyloxy groups can be those of any carboxylic acidcustomarily employed in the steroid chemistry for esterificationreactions. Preferred acids are those of up to carbon atoms,'especiallylower and intermediate hydrocarbon carboxylic acids of 2-12 carbonatoms. However, the acids can also be unsaturated, branched, polybasic,unsubstituted or substituted in the usual manner, for example by ahydroxy group, an amino group, or one or more halogen atoms. Suitableare also cycloalkanoic, hydrocarbonaryl, mixed hydrocarbonaryl-alkanoic,cycloalkylalkanoic and heterocyclic carboxylic acids which can likewisebe substituted in the usual manner with 1,2 or 3 simple substituents.Preferred acids for forming the acyloxy residues R R and/or R are, forexample, alkanoic acids, e.g., acetic acid, propionic acid, valericacid, caproic acid, enanthic acid, undecylic acid, oleic acid,trimethylacetic acid, haloacetic acids, e.g., trichloroacetic acid,cycloalkylcarboxylic and cycloalkylalkanoic acids, e.g.,cyclopentylpropionic acid, arylalkanoic acids, e.g., phenylpropionicacid, phenylacetic acid, and substituted alkanoic acids, e.g.,phenoxyacetic acid, dialkylaminoacetic acid, piperidinoacetic acid,succinic acid, benzoic acid, etc.

Because of their known usefulness in steroid pharmaceutical chemistry,the preferred reaction products of the present invention are accordingly9a-H-steroids of the general Formula 111, wherein X is H.

The process of this invention is suitably conducted by adding thetrialkyltin hydride to a solution of the starting steroid dissolved in asuitable inert solvent.

Examples of suitable trialkyltin hydrides are those wherein alkyl is of1 10, preferably 1 6 carbon atoms, e.g., trimethyltin hydride,triethyltin hydride, and tributyltin hydride, the latter being preferredsince it can be handled relatively easily.

At least the latter portion of the reaction is preferably conducted inthe presence of a free radical. However, the reaction of this inventioncan also be accomplished in the absence of a free radical-forming agent,although longer reaction times sometimes are necessary. Examples ofsuitable free radical-forming agents are azodiisobutyronitrile,di-tert.-butyl peroxide and UV irradiation.

The process of this invention can also be conducted, if desired, byforming the trialkyltin hydride in situ during the reaction. For thispurpose, the corresponding trialkyltin oxide and polymethylsiloxane areadded to a solution of the starting steroid. The advantage of thismodification of the process is that easily decomposed trialkyltinhydrides need not be isolated in an initial step.

.Suitable solvents for the process of this invention are those which areinert with regard to the reactantsExamples are the ethers, such asdiethyl ether or glycol ether, cyclic ethers, such as tetrahydrofuran ordioxane and hydrocarbons, such as hexane or benzene. Also suitable arealcohols, such as ethanol or glycol and nitriles, such as acetonitrile.I

Theprocess of this invention is preferably effected at an elevatedtemperature, i.e., from above room temperature to the boiling point ofthe reaction mixture, e.g., from about 20 to 100C. However, the reactionalso occurs below room temperature, but the reaction times in some casesbecome very long.

The compounds producible in accordance with this invention are eitherthemselves valuable pharmaceuticals, such as, for exampleantiphlogistics, or they are intermediates for the preparation of suchpharmaceuticals- The following illustrates the effect of triphenyltinhydride on the 6a-fluoro atom.

EXAMPLE A 2. 3 g. of 6afluoro-9a-bromo-l l B-hydroxy-Z l valeryloxyl6a-methyl-1 ,4-pregnadiene-3 ,20-dione (produced conventionally from6a-fluoro-2 l valeryloxyl 6a-methyl-1 ,4,9( l 1 )-pregnatriene-3 ,20-

dione by treatment with N-bromosuccinimide in aque ous dioxane) isdissolved in 46 ml. of tetrahydrofuran and combined with 14.5 ml. oftriphenyltin hydride and 50 50mg. of azodiisobutyronitrile. Afterheating for 20 minutes to 80 C., the reaction mixture is concentratedunder vacuum and the residue is chromatographed on silica gel. With21-26% acetone-hexane, and after recrystallization from acetone-hexane,the product was 1.20 g. of llB-hydroxy-2l-valeryloxy-l6a-methyl-l,4-pregnadiene-3,20-dione, m.p. l52.5 l53.0 C. [011 +l20 (chloroform); UV:e 14,800 (methanol).

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 a. 2.0 g. of 6a-fluoro-2l-valeryloxy-l6a-methyl- 1,4,9( 1 l)-pregnatriene-3,20-dione is dissolved in 80 ml. of dioxane and 20 ml.of water and combined with 2.0 g. of N-bromosuccinimide as well as 2.0ml. of strength perchloric acid. The reaction mixture is agitated for 3hours at room temperature and then precipitated with water whichcontains sodium sulfite. The thus-produced precipitate isvacuum-filtered and dissolved in methylene chloride. The solution iswashed with water, dried over sodium sulfate, and evaporated undervacuum, thus obtaining 2.4 g. of 6a-fluoro-9abromo-l l B-hydroxy-Z l-valeryloxyl fia-methyl-l ,4- pregnadiene-3,20-dione as a crude product.

b. 2.4 g. of the thus-obtained product is dissolved in 48 ml. oftetrahydrofuran and mixed with 17 ml. of tributyltin hydride. Themixture is heated to C. and, after 2 hours of reaction, 10 mg. ofazodiisobutyronitrile is added thereto. After another hour, the reactionis terminated. The solution is evaporated under vacuum and the residuecrystallized with hexane. The crystalline, product is filtered off andrecrystallized from acetone/hexane. Yield: 1.83 g. of 6a-fluoro-1IB-hydroxy-2 l -valeryloxyl 6a-methyl-l ,4-pregnadiene- 3,20-dione, m.p.201.6 C. [0 114 (chloroform); UV: e 16,000 (methanol).

EXAMPLE 2 a. 1.5 g. of 6wfluoro-2l-trimethylacetoxy-ltiamethyl-l ,4,9( 11 )-pregnatriene-3,20-dione is converted into the bromohydrin under theconditions described in Example 1(a). Yield: 1.7 g. of6oz-fluoro-9oz-bromo- 1 1,8-hydroxy-2l-trimethylacetoxy-l60r-methyl1,4-pregnadiene-3,20-dione as the crude product.

b. 1.7 g. of the thus-obtained product is dissolved in 37.5 ml. oftetrahydrofuran. The solution is mixed with 3.75 ml. of tributyltinhydride and 0.05 ml. of di-tert.- butyl peroxide and heated to theboiling point for 30 minutes. The reaction mixture is then evaporatedunder vacuum and the residue triturated with hexane. The crystallineslurry is vacuum-filtered and recrystallized from acetone/hexane. Yield:1.32 g. of 6oz-fluorol 1B-hydroxy-21-trimethylacetoxy-16oz-methyl-1,4-pregnadiene-3,20-dione, m.p. 169.5 C. [a] 103 (chloroform); UV: E24115,200 (methanol).

EXAMPLE 3 2.2 g. of6a-f1uoro-9oc-chloro-11B-hydroxy-16ozmethyl-l,4-pregnadiene-3,20-dione(US. Pat. No.

3,426,128) is dissolved in 40 ml. of tetrahydrofuran; the solution isheated to the boiling point for 3 hours after combining with 10 ml. oftributyltin hydride and 50 mg. of azodiisobutyronitrile. The reactionmixture is evaporated under vacuum and the residue triturated withhexane. The crystalline product is isolated and recrystallized fromacetone/hexane. Yield: 1.73 g. of 601- f1uoro- 11/3-hydroxy-2l-hexanoyloxy-l6oz-methyl-1,4- pregnadiene-3,20-dione, m.p.243.2C. [a] 118 (chloroform); UV: 15,100 (methanol).

EXAMPLE 4 2.41 g. of 6oz-fluoro-9a-bromo-1 1,8-hydroxy-21-acetoxy-16a-methyl-1 ,4-pregnadiene-3,20dione (lDAS 1,211,194) isdissolved in 48 ml. of tetrahydrofuran. The solution is heated for 5hours to the boiling point after adding 4.8 ml. of tributyltin hydride.After the solvent has been evaporated, the residue is treated withhexane, the crystalline product is isolated and recrystallized fromacetone/hexane. Yield: 1.69 g. of 60:- fluoro-l1,8-hydroxy-2l-acetoxy-160z-methyl-1,4-pregnadiene-3,20-dione, m.p.230.3 C. [011 117 (chloroform); UV: 6 15,800 (methanol).

EXAMPLES 2.5 g. of6oz-fluoro-9oz-bromo-l1,8-hydroxy-2lacetoxy-16oz-methyl-4-pregnene-3,20-dione(DAS 1,211,194) is dissolved in 50 ml. of tetrahydrofuran and combinedwith 10 ml. of tributyltin hydride as well as 50 mg. ofazodiisobutyronitrile. The mixture is heated for 30 minutes to theboiling point, the solution is concentrated under vacuum, and theresidue is triturated with hexane. The crystalline product is isolatedand recrystallized from acetone/hexane. Yield: 1.93 g. of 60z-fluor0-llB-hydroxy-Zl-acetoxy-16a-methy1-4- pregnene-3,20-dione, m.p. 259.7 C.[th, 168 (chloroform); UV: e 14,700 (methanol).

EXAMPLE 6 750 mg. of 6a-fluoro-9a-bromo-l1B,l7oz-dihydroxy- 21-acet0xy16a-methyl-1 ,4-pregnadiene-3 ,20-dione (JACS 82, 2318 [60]) is reactedwith tributyltin hydride under the conditions described in Example 5.The crude product is recrystallized from acetone/hexane. Yield: 478 mg.of 6a-f1uoro-1113,17a-dihydroxy-2lacetoxy-l 60z-methyl-l,4-pregnadiene-3,ZO-dione, m.p.

241.3 C. [01] 74 (chloroform); UV: 6 15,800 (methanol).

EXAMPLE 7 950 mg. of 6o1-fluoro-9oz-bromo-1 1,8,17ct-dihydroxy-21-acetoxy- 1 ,4-pregnadiene-3,20-dione (DAS 1,090,661) is reduced withtributyltin hydride under the conditions disclosed in Example 5. Thecrude product is recrystallized from acetone/hexane. Yield: 655 mg. of6or-fluoro-l 18,17cz-dihydroxy-2l-acetoxy-l ,4- pregnadiene-3,20-dione,m.p. 241 .0 C. [a] (dioxane) UV: 6 17,000 (methanol).

EXAMPLE 8 500 mg. of 60i-fltl0l0-90i-bl'0l'IlO-l lB-hydroxy-1601,17oz-isopropylidenedioxy-2l-acetoxy-1 ,4-pregnadiene-3,20-dione(Steroids 7, 381 [66]) is reacted with tributyltin hydride under theconditions set forth in Example 5. The crude product is recrystallizedfrom acetone/hexane. Yield: 338 mg. of 6oz-fluoro-1 1,8-hydroxy-160:,17a-isopropylidenedioxy-2l-acetoxy-l ,4-pregnadiene-3,20-dione, m.p. 271.0 C. [(11 89 (chloroform); UV: e 16,100(methanol).

XAMPLE 9 350 mg. of 6oz-fluoro-9a-bromo-l IB-hydroxy-1704,21-diacetoxy-4-pregnene-3,20-dione (JACS 82, 3399 [60]) is reducedwith tributyltin hydride in accordance with the conditions described inExample 5. After recrystallization of the crude product from methylenechloride/diisopropyl ether, the yield is mg. of 6oz-fluoro-1lB-hydroxy-17a,2l-diacetoxy-4-pregnene- 3,20-di0ne, m.p. 231.1 C.

EXAMPLE 10 mg. of 60z-fluoro-901-bromo-l 1fi,17oz-dihydroxy-2l-acetoxy-21-methyl-1,4-pregnadiene-3 ,20-dione (US. Pat. No.3,047,594) is reduced with tributyltin hydride under the conditionsdisclosed in Example 5. The crude product, after recrystallization fromacetone/hexane, yields 79 mg. of 60z-fluoro-1 13,1712-dihydroxy-21-acetoxy-21-methyl- 1 ,4-pregnadiene- 3,20-dione, m.p. 223.0C.

EXAMPLE 1 1 200 mg. of 6oc-fluoro-9oz-br0mo-l l,8,170z-dihydroxy-2l-acetoxy-16,8-methyl-1,4-pregnadiene-3,20-dione (German Patent1,443,176) is converted into 60:- fluoro-l 1 ,8,17a-dihydroxy-2l-acetoxyl 6,8-methy1- 1,4-pregnadiene-3,20-dione under the conditionsindicated in Example 5. Yield: 113 mg., m.p. 2l5.5 C.

EXAMPLE 12 scope thereof, can make various changes and modifica tions ofthe invention to adapt it to various usages and conditions.

What is claimed is:

1; A process for the selective dehalogenation of the 9-halogen atom of6a-fluoro-9a-halo-l IB-hydroxy-N- and A -3-keto steroids wherein halo isCl, Br or I, which comprises dehalogenating with a trialkyltin hydride.

2. A process according to claim 1 wherein the trialkyltin hydride istributyltin hydride.

3. A process according to claim 1 wherein at least the latter portion ofthe reaction is conducted in the presence of a free radical.

4. A process according to claim 3 wherein the reaction is conducted inthe presence of di-tert.-butyl peroxide or azodiisobutyronitrile.

5. A process according to claim 1 wherein the reaction is conducted at atemperature from above room temperature to the boiling point of thereaction mixture.

6. A process according to claim 5 wherein'the trialkyltin hydride istributyltin hydride and at least the latter portion of the reaction isconducted in the presence of free radicals and the 9-halogen atom isbromine.

7. A process according to claim 1 wherein the starting steroid is acompound of the formula wherein R is hydrogen, hydroxy or acyloxy, R ishydrogen, hydroxy or acyloxy and R is hydrogen, methyl, hydroxy oracyloxy, acyloxy in each instance being the acyl radical of ahydrocarbon carboxylic acid of 2-12 carbon atoms, or R and Rcollectively are dialkylmethylenedioxy wherein alkyl is of l 4 carbonatoms, R is hydrogen or methyl, X is cl, Br or I, and C,=-;C are the Cand C -p0sition carbon atoms joined by'a single or doublecarbon-to-carbon bond.

8. A process according to'claim 7 wherein'the trialkyltin hydride istributyltin hydride and at least the latter portion of the reaction isconducted in the presence of free radicals and the 9-halogen atom isbromine.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. I 3,894,063

DATED 3 July 8, 1975 INVENTOR( I HENRY LAURENT and RUDOLF WIECHERT it iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Claim 7 (column 8, line 24), delete "01" and insert -C1-.

Signed and Scaled this eighreenth D ay Of November 1 9 75 [SEAL] Arrest:

RUTH C. MASON f. MARSHALL DANN xlIIA'SIIIIX ()jjr've'r (ummminnvr n]luu'nrs and Trutlmnurks

1. A PROCESS FOR THE SELECTIVE DEHALOGENATION OF THE 9-HALO GEN ATOM OF 6A-FLUORO-9A-HALO-11B-HYDROXY-$4- AND $1.4-3KETO STEROIDS WHEREIN HALO IS CI, BR OR I, WHICH COMPRISES DEHALOGENATING WITH A TRIALKYTIN HYDRIDE.
 2. A process according to claim 1 wherein the trialkyltin hydride is tributyltin hydride.
 3. A process according to claim 1 wherein at least the latter portion of the reaction is conducted in the presence of a free radical.
 4. A process according to claim 3 wherein the reaction is conducted in the presence of di-tert.-butyl peroxide or azodiisobutyronitrile.
 5. A process according to claim 1 wherein the reaction is conducted at a temperature from above room temperature to the boiling point of the reaction mixture.
 6. A process according to claim 5 wherein the trialkyltin hydride is tributyltin hydride and at least the latter portion of the reaction is conducted in the presence of free radicals and the 9-halogen atom is bromine.
 7. A process according to claim 1 wherein the starting steroid is a compound of the formula
 8. A process according to claim 7 wherein the trialkyltin hydride is tributyltin hydride and at least the latter portion of the reaction is conducted in the presence of free radicals and the 9-halogen atom is bromine. 